Physiological elevations of plasma free fatty acids (FFA) have been shown to produce insulin resistance dose-dependently in healthy and in diabetic subjects and to increase insulin secretion chronically in healthy subjects. However, FFA stimulated insulin secretion less in diabetic (NIDDM) than in non-diabetic subjects. These findings suggested that in most obese subjects, FFA increased insulin secretion sufficiently to compensate for the insulin resistance that they had generated and thus prevented deterioration of glucose tolerance. The objective of the current project is to determine the reason why a minority of obese subjects develop diabetes (NIDDM). Specifically, we plan to test the hypothesis 1) that in obese subjects, who are genetically predisposed to develop NIDDM, FFA fail to appropriate stimulate insulin secretion and 2) that this would then leave peripheral and hepatic insulin resistance, at least partially, uncompensated, resulting in NIDDM. To test this hypothesis, we propose to study effects of a wide spectrum of a wide plasma FFA concentrations on insulin secretions in 3 groups of subjects, representing 3 stages in the development of NIDDM. The 3 groups will consist of 1) first degree relatives of patients with NIDDM. These subjects are normally glucose tolerant, but are considered to be at high risk to develop NIDDM; 2) subjects who have impaired glucose tolerance, i.e., individuals in whom glucose tolerance has not yet deteriorated to the point of frank diabetes and 3) patients with newly diagnosed NIDDM (< 1 year). In all subjects, plasma FFA levels will be either lowered (with nicotinic acid, Test 1) or maintained at basal levels (with saline plus glycerol, Test 2) or increased (with IV lipid plus heparin, Test 3). Plasma glucose concentrations will be clamped at euglycemic levels (all subjects). To assess hepatic actions FFA in more detail we will test effects of elevated plasma FFA (IV lipid/heparin) on rates of gluconeogenesis and glycogenolysis in patients with NIDDM and controls. NIDDM affects between 20 and 30% of the elderly population in the US and is responsible for a large amount of morbidity and mortality. We hope that this project will help to better understand the mechanisms by which obesity contributes to the development of NIDDM.